A New Symmetrical Thiazolidinedione Derivative: In Silico Design, Synthesis, and In Vivo Evaluation on a Streptozotocin-Induced Rat Model of Diabetes

Samuel Álvarez-Almazán,Jessica Elena Mendieta-Wejebe,Itzia Irene Padilla-Martínez,Feliciano Tamay-Cach,Gabriel Navarrete-Vázquez,José Correa-Basurto,Diana Alemán-González-Duhart

doi:10.3390/pr9081294

Abstract

By activating PPAR-γ, thiazolidinediones normalize glucose levels in animal models of type 2 diabetes and in patients with this pathology. The aim of the present study was to analyze 219 new derivatives in silico and select the best for synthesis, to be evaluated for acute oral toxicity in female rats and for control of diabetes-related parameters in a rat model of streptozotocin-induced diabetes. The best compound was chosen based on pharmacokinetic, pharmacodynamic, and toxicological parameters obtained in silico and binding orientation observed by docking simulations on PPAR-γ. Compound 1G was synthesized by a quick and easy Knoevenagel condensation. Acute oral toxicity was found at a dose greater than 2000 mg/Kg. Compound 1G apparently produces therapeutic effects similar to those of pioglitazone, decreasing glycaemia and triglyceride levels in diabetic animals, without liver damage. Moreover, it did not cause a significant weight gain and tended to reduce polydipsia and polyphagia, while diminishing systemic inflammation related to TNF-α and IL-6. It lowered the level of endogenous antioxidant molecules such as reduced glutathione and glutathione reductase. In conclusion, 1G may be a candidate for further testing as an euglycemic agent capable of preventing the complications of diabetes.

Highlights

Diabetes is a complex and progressive metabolic disorder capable of generating a dreadful health condition
The process of drug design and development is a long and costly process, especially when a wide range of possibilities exist for modifying the ligands of a given receptor
The 219 compounds (Table S1, Supplementary Material) designed were examined in silico to find the best candidate for further research

Summary

Introduction

Diabetes is a complex and progressive metabolic disorder capable of generating a dreadful health condition. It derives from low or absent insulin activity [1] that results in hyperglycemia, defined as a blood glucose level above 126 mg/dL. When chronic, the latter condition triggers insulin resistance and many other possible long-term complications, including cardiovascular disease, diabetic nephropathy, and loss of vision. The decrease in insulin secretion by β-pancreatic cells contributes to the chronic state of hyperglycemia [2], a condition resulting from the incapacity of glucose to cross the plasma membrane. There is a poor translocation of glucose transporter type 4 (GLUT-4) to the membrane [1,3]

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